Our laboratory is elucidating the nature of the immune response to tumors and establishing principles which may enhance our ability to immunize patients against known tumor antigens and induce tumor regression with cytokine therapy. We have developed methodologies for identifying tumor-specific CTL from patients with renal cell cancer and successfully used these techniques to identify unmutated FGF-5 as an HLA-A3 restricted antigen on RCC, recognized by T-cells. There is now an active clinical protocol immunizing patients with RCC with peptides from FGF-5. Continuing these efforts looking at other antigens expressed on RCC, we have found tumor-reactive T-cells in patients with RCC which recognize their own tumors as well as allogeneic RCCs. Some of these cells have unusual reactivity profiles and novel recognition mechanisms tumors. We are studying a CD4 clone that recognizes nearly all RCC regardless of classical MHC type yet utilizes the T-cell receptor. This class of T-cells could be a valuable reagent for addressing tumors which have lost MHC expression. Finally, we have also activated a protocol in which patients will be treated with their RCC-reactive T-cells discovered through these efforts.